The present invention relates to a quick dissolving or disintegrating solid product or dosage form intended for a wide variety of uses, including oral administration to a patient to achieve a desired therapeutic response.
Patient compliance remains a significant problem in health care. Compliance is dependent on a number of factors including but not limited to the route and frequency of drug administration. Frequency of administration can sometimes be decreased by administering long-acting, sustained release, or controlled release pharmaceutical formulations. These techniques have been of tremendous benefit, especially for oral administration. However, oral dosage forms themselves oftentimes have serious disadvantages that adversely affect patient compliance.
Oral dosage forms remain a significant problem for a significant segment of the population. Many patients are unable or unwilling to swallow a solid dosage form. This problem occurs primarily in children and the elderly, however, problems with swallowing are not limited to those segments of the population. Certain conditions or disease states manifest themselves by swallowing difficulties. Otherwise healthy individuals can also exhibit problems with swallowing. Such swallowing difficulties irrespective of their cause can severely compromise patient compliance. In addition, swallowing difficulties are not limited to humans and swallowing remains a significant issue in medicating animals.
The pharmaceutical industry has long-recognized the need for a form of oral administration which avoids the swallowing difficulties associated with a traditional tablet. Syrups, elixirs, microcapsules containing slurries, chewable tablets and other novel tablet or capsule dosage forms have been developed. None of these dosage forms have been ideal and each has their own disadvantages. The disadvantages include a more costly process for preparation and/or more costly packaging materials.
A number of researchers have described a wide variety of techniques for obviating or minimizing swallowing problems. Aikire et al, U.S. Pat. No. 5,607,697 discloses an oral dosage form which is composed of a plurality of microparticles each having a core including an active ingredient and a compound which is sweet in taste and has a cooling sensation. Such a compound can be selected from the group consisting of mannitol, sorbitol, a mixture of artificial sweetener and menthol, a mixture of a sugar and menthol or methyl salicylate.
Another solution to this problem was described in Wehling et al., U.S. Pat. No. 5,178,878 which relates to certain effervescent dosage forms containing microparticles. The effervescent dosage forms of Wehling et al. provide an effervescent dosage form for direct oral administration. The dosage form is designed to disintegrate rapidly in the mouth releasing its microparticles as a slurry for ingestion. The dosage forms produced in accordance with Wehling et al. can be placed in the patient""s mouth and the effervescence contained therein can be activated on contact by the patient""s saliva. The tablet then disintegrates.
Kxc3xa4llstrand, et al., U.S. Pat. No. 4,994,260 relates to a pharmaceutical mixture. The mixture is used for the controlled release of a substance. According to Kxc3xa4llstrand, et al., a liquid dosage form is produced using either a dry powder or microcapsules which are suspended in a solution of a release-controlling substance, also referred to as a xe2x80x9csink.xe2x80x9d Alternatively, it is possible to encapsulate the release-controlling substance, together with a drug, within an encapsulating shell. The release-controlling substance may include, inter alia, carbohydrates and carbohydrate-related compounds, disaccharides, monosaccharides, glycerol, glycol, glycosides of monosaccharides and substances derived from ethylene glycol.
Boder et al., U.S. Pat. No. 5,126,151 relates to an encapsulation mixture. Boder et al. refers to the construction of gums and candies in oral dosage forms. According to Boder et al., microcapsules are produced using a core material which can be selected from a wide variety of materials including sweeteners, medicaments, drugs, flavoring agents and the like. These materials can be used, either singularly or in combination, in either a single or multiple part delivery system. That is, one or more of these materials may be present within one coating matrix or may be separately coated by the matrix and employed alone or in combination in the final product. The resulting formulations are said to provide a masking of unpleasant tasting drugs such as potassium chloride and the like, thereby making consumption of the drug more appealing to the patient. The dosage forms may be prepared in chewable tablet form.
Also of interest may be Schobel et al., U.S. Pat. No. 4,824,681, and Wei et al., U.S. Pat. No. 4,590,075. Encapsulated sweeteners have also been used to provide an extended release of sweetening in, for example, chewing gum.
Cousin et al., U.S. Pat. No. 5,464,632 discloses a rapidly disintegratable tablet for oral administration with or without the use of water. The tablet comprises an active substance and a mixture of excipients, wherein the active substance is multiparticulate and in the form of coated microcrystals, coated microgranules or uncoated microgranules and wherein the mixture of excipients comprises excipients which are responsible for the disintegration. The tablet is intended to be swallowed and disintegration occurs in less than sixty seconds under the action of excipients which are responsible for disintegration and which are selected from the group consisting of at least one disintegrating agent and at least one swelling agent.
Cherukuri et al., U.S. Pat. No. 5,587,172 is directed to a comestible unit which disperses quickly in the mouth and is prepared by subjecting a feedstock comprising a carbohydrate capable of undergoing flash-flow processing without use of a solution to provide a shearform matrix; initiating crystallization of the shear/form matrix; forming flowable compactible micro-particulates by combining an additive with the shearform matrix; and compacting the micro-particulates to form the final unit.
Gole et al., U.S. Pat. No. 5,558,880 is concerned with a method for preparing a solid, porous delivery matrix comprising a porous network of matrix material that disperses rapidly in water. The matrix material comprises a matrix forming agent and one or more amino acids having from about 2 to 12 carbon atoms. The matrix material dispersion is then lyophilized or subjected to solid-state dissolution to form the solid, porous delivery matrix.
A number of companies have attempted to develop a quick dissolving oral tablet using lyophilization techniques. A number of disadvantages are also associated with those products. First, water-dissolving compounds interfere with the freeze-dry cycle. Second, the product oftentimes has an unpleasant or bad taste and, third, the lyophilization process itself is time-consuming and expensive. A lyophilized formulation cannot be used with water soluble active ingredients and is limited to low dosages of active ingredients. Further, these tablets are very fragile requiring special packaging procedures thereby increasing the cost of the final product.
Yet another manufacturer uses effervescence to create a quick dissolving tablet. Carbon dioxide is generated within the tablet in order to blow the tablet apart. Once again, the tablets prepared by this process are very fragile and require special and costly packaging procedures.
Another manufacturer utilizes spun sucrose (xe2x80x9ccotton candyxe2x80x9d) as a quick dissolving tablet matrix. This is an undesirable technology because of the hydroscopic nature of spun sucrose. The resultant tablets are very fragile and require special packaging.
Yet others have dissolved a preparation of a 3% gelatin bead using a spray-dried process. This is not very efficient in terms of throughput. Animal gelatin and sugars are used to prepare a spray-dried bead which is mixed with other ingredients and tablets are stamped out using a tableting machine.
There remains a need in the art for quick dissolving oral tablets, i.e., tablets which dissolve and/or disintegrate, without the need for water or a liquid, in the mouth of a patient. Water or another suitable liquid may not be convenient or readily available or a patient may experience difficulty swallowing. In either situation it would be desirable to use a tablet which can incorporate a large amount of an active ingredient or drug optionally along with taste-masking excipients and also the release of the active ingredient upon contact with the surface of the mouth.
Thus, while the art has long-struggled with developing a more desirable oral pharmaceutical dosage form, there remains a long-felt need for an improved oral dosage form.
An object of the present invention is to develop a relatively quick dissolving or disintegrating oral dosage form that disintegrates in the mouth within approximately 60 seconds, preferably less than ten seconds, and has acceptable mouth feel.
A further object of the present invention is to develop a tablet for oral administration with superior taste, convenient administration and a high load of active ingredient per unit dose without the need for expensive packaging procedures.
It is also a primary object of the present invention to prepare a finished product which readily disintegrates or dissolves upon exposure to an aqueous environment. Such a product would be especially useful in a wide variety of applications, including but not limited to the delivery of pharmaceutical products to a patient, including sterile ophthalmic solutions, food application, such as confections including a nugget bar or the like, veterinary uses including a chunk of material intended to be licked by an animal: cosmetics, diagnostics, sanitation of water or water products, carriers for pigments (paint), dispersants for dyes, agricultural uses including fertilizers, herbicides and the like, preparation of a mold or model material and the like.
The mixture of excipients in the rapidly disintegratable tablet provide desirable mouthfeel characteristics and physical properties when the tablet is sintered. Further objects and embodiments of the present invention will be made known in the following description of the preferred embodiments and claims. Though the following description of the preferred embodiments focuses on the inclusion of pharmaceuticals as the active agents, it is to be understood that the desirable properties of the inventive methods and dosage forms may be advantageously used in connection with many different types of active agents.
In accordance with the present invention, there is provided a rapidly disintegratable or quick dissolving product which releases a functional or active ingredient upon exposure to an aqueous environment. The product comprises at least one functional or active ingredient and a mixture of excipients, wherein said excipients provide desired characteristics and physical properties such that when the product is sintered or heated, excellent binding characteristics are obtained.
There is also provided a rapidly disintegratable or quick dissolving product. This product is advantageously useful for administration with or without the use of water, said product comprising at least one functional or active ingredient and a mixture of excipients, wherein said excipients provide desired characteristics and physical properties such that when the product is sintered or heated, excellent binding characteristics are obtained. The product is preferably a tablet which is intended to disintegrate in the mouth or in the presence of an aqueous environment. The mixture of excipients in the rapidly disintegratable product preferably provide desirable mouthfeel characteristics and physical properties when the tablet is sintered or heated. The sintering or heating is preferably conducted at approximately 50xc2x0 C. to 120xc2x0 C. The mixture can contain at least one binding agent and the binding agent is preferably polyethylene glycol having a molecular weight of approximately 1,000 to 1 million. The rapidly disintegratable product preferably contains a structural agent, preferably gelatin, more preferably fish gelatin.
Applicants have also discovered a process for the preparation of a rapidly dissolvable or disintegratable tablet as described above for use with or without water. Release of the active ingredient simply requires exposure to an aqueous environment.
The process comprises dissolving at least one bulking agent and at least one structural agent in a suitable solvent, wherein said solvent provides high porosity upon drying; spray-drying or dispersing said dissolved mixture to obtain a granulated product which can also be referred to as a matrix or bead; dry blending at least one binding agent, and at least one active ingredient with the granulated product to obtain a preformulation product or adding at least one active ingredient to the dissolved components before drying; optionally compressing said preformulation to obtain a form such as a tablet; and sintering or heating said preformulation for a sufficient time and temperature to allow the binding agent to change status or melt and allow said binding agent to resolidify as the temperature is reduced to ambient temperature. The active ingredient may be added to the solvent, the dissolved components or the dry blended mixture. The binding agent may be added to the bulking agent, the structural agent, the combined bulking agent and structural agent or dry blended along with the bead or granulated product to obtain a preformulation product.